Liver disease is a major cause of morbidity and mortality and the prognosis is often poor. In many liver diseases (such as viral hepatitis, autoimmune hepatitis and alcoholic liver disease), activated T lymphocytes and macrophages appear to play an important role in liver damage. Autoimmune hepatitis is an inflammatory liver disease characterized by the presence of high transaminases, circulating autoantibodies, hypergammaglobulinemia, histological evidence of hepatitis and responsiveness to immunosuppressive treatment. In autoimmune hepatitis, activated T cells and macrophages either directly attack liver parenchymal cells or induce tissue damage by the release of several proinflammatory cytokines, such as TNF-α and IFN-γ.
The precise cause of autoimmune hepatitis is not clear. Environmental agents assumed to induce autoimmune hepatitis have not been delineated but include viruses and bacteria. The finding of molecular mimicry by cross-reactivity between epitopes of viruses and certain liver antigens adds credence to a hypothesis of virally triggered disease. Because the trigger or triggers of autoimmune hepatitis may be part of a so-called hit-and-run phenomenon, in which induction occurs many years before overt autoimmune disease, identifying an infectious agent may prove impossible. However, evidence does exist implicating measles virus, hepatitis viruses, cytomegalovirus, and Epstein-Barr virus as initiators of the disease; with the most convincing evidence related to hepatitis viruses. Autoimmune hepatitis is more common among women than men, but it occurs globally in children and adults of both sexes in diverse ethnic groups. Since chronic viral hepatitis appears to be very common, the prevalence of autoimmune hepatitis may be higher than reported because of concomitant chronic hepatitis C or B or both. Certain drugs, including oxyphenisatin, methyldopa, nitrofurantoin, diclofenac, interferon, pemoline, minocycline, and atorvastatin, can induce hepatocellular injury that mimics autoimmune hepatitis.
There are three experimental mouse models of T cell dependent liver injury. D-galactosamine (GalN)-sensitized mice challenged with either T cell activating anti-CD3 monoclonal antibody (mAb) or with the superantigen staphylococcal enterotoxin B (SEB) developed severe liver injury characterized by internucleosomal DNA fragmentation as well as by histological hallmarks of hepatocyte apoptosis, both preceding the increase of plasma transaminases. Administration of the T cell mitogen concanavalin A (Con A) to unsensitized mice also resulted in hepatic apoptosis and the ensuing necrosis. Anti-CD3 mAb as well as SEB or Con A induced the release of systemic tumor necrosis factor (TNF), interferon gamma (IFN-γ), and various other cytokines. T lymphocytes were identified as effector cells of Con A in vivo by proof of resistance of athymic nude mice against Con A and by restoration of susceptibility in nude mice by lymphocyte transfer from control mice. Moreover, antibody-dependent depletion of CD4+ T cells fully protected against Con A. These results indicated that cytokines released following T helper cell activation mediated liver injury. Con A-induced liver damage mimics human viral and autoimmune hepatitis in many aspects. These include an increase in the serum concentration of several cytokines including TNF-α, IFN-γ, IL-6, and IL-1. During the early stages, TNF-α and IFN-γ directly mediate liver cell damage. The cell types involved in the induction of Con A-induced hepatitis include neutrophils, CD4+ T cells, CD8+ T cells, αβT, NK T cells and Kupfer cells which have been directly implicated in autoimmune, viral, alcoholic hepatitis, and ischemia/reperfusion injury.
Autoimmune hepatitis in humans is classified as either type I or II, based on the presence of anti-nuclear (ANA) and/or smooth muscle (SMA) antibodies in type I, and liver/kidney microsomal antibody for type II. The ten-year survival rate in untreated patients is approximately 10%. Both types of autoimmune hepatitis are treated with corticosteroids such as prednisone as well as other immunosuppressive drugs such as azathioprine, mycophenylate mofetil, cyclosporine or tacrolimus. Patients who progress to end stage liver disease and/or cirrhosis may also need a liver transplant. Therefore, alternative treatment options are needed. Therapeutic approaches that either inhibit immune-mediated mechanisms or directly inhibit liver cell damage show promise. These studies have addressed the mechanism underlying use of CAM therapy in ameliorating hepatitis and liver damage. While extensive studies have been performed to elucidate the mechanism of viral hepatitis, there is paucity of information on the pathogenesis of autoimmune hepatitis and a dire need for the development of CAM therapy to treat such patients.
Complementary and alternative medicine (CAM) is popular amongst patients with hepatitis. A recent survey conducted in liver disease outpatient clinics in the US found that 41% had used some form of CAM at least once during the preceding 4 weeks. The CAM therapies tried out clinically include antioxidants, thymic extract, zinc, Chinese herbs, Glycyrrhiza glabra (licorice), and Oxymatrine (derived from Sophora japonica). Several herbal medicinal products and supplements have been identified with potential virological and/or biochemical effects in the treatment of chronic hepatitis C infection. Studies of thymic extract, zinc and Bing Gan decoction in combination with interferon-□ and oxymatrine alone have demonstrated greater clearance of the hepatitis C virus than control treatment. Normalization of liver enzymes has been greater during treatment with vitamin E, Glycyrrhiza glabra, CH100, Yi Zhu decoction and Yi Er Gan Tang decoction than with the control treatment. Evidence suggests that many more complementary therapies are currently available to and popular with patients and further research into these interventions is warranted to establish their role in the treatment of hepatitis.